JPH03173823A - Vitamin b12s-containing composition - Google Patents

Abstract

PURPOSE:To obtain the subject composition having excellent mixing stability by dispersing vitamin B12s in a mixture of starch and dextrin. CONSTITUTION:Vitamin B12s such as cyanocobalamin, hydroxocobalamin or coenzyme-type vitamin B12 are dissolved in water or an aqueous organic solvent diluted with water, then resultant solution is added to a mixture of starch and dextrin, thus mixed to obtain uniform dispersion of vitamin B12s and dried. 0.05-1.0wt.%, especially 0.1-1.0wt.% vitamin B12s and 5-30wt.%, especially 10-20wt.% dextrin are suitably contained in the composition.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention is stable and can be used in powders, fine granules, granules, capsules, tablets, etc. in the fields of food, medicine, livestock feed, etc. Inexpensive vitamin BI! The present invention relates to compositions containing .

Conventional technology Generally, vitamin B1 is added to solid preparations such as pharmaceuticals.
Category 2 is in extremely small amounts. For example, according to the Approval Standards for Manufacturing (Importing) Vitamin Drug Preparations (February 1, 1988), the daily administration or blending amount of dianocobalamin and hydroquincobalamin is 1 to 1500 μg.

Therefore, in order to make the content uniform, vitamin B12 is adsorbed on an inert excipient (for example, lactose, starch, etc.); It is used as a multiplication factor.

Currently, products that are actually commercialized using such inert excipients include mannitol adsorbent powder (ME
RCK, Vitamin B 11-Mannit-
Verreibung 0, 1%), lactose adsorption powder (V
ERCK.

Vita+iin B B-Lactose-Verr
eibung O, 1%) and dicalcium phosphate adsorption powder (H, REISMAN CORPORATTON,
CYANOCOBALAMIN, USP O, 1%
TRITURATION W/DIBASIC CALC
IUM PH05PHATE).

Furthermore, it is known that the stability of vitamin B12s generally decreases when they are diluted, and their compatibility with other drugs or additives is poor. For example, according to Eva and Campell et al., it is known that vitamin El+z becomes unstable in the presence of ascorbic acid, nicotinamide, thiamine, talc, sucrose, metal ions, etc. (Cam
pbell, J.A.;J.

Pharm, Sci; 44.263, 1955)
.

For these reasons, in order to incorporate vitamin B12 into solid preparations, it is necessary to use stable adsorption bundles as mentioned above or other methods in order to separate them from other drugs or ensure uniformity of content. Methods have been used, such as preparing one group by mixing with other drugs, and separating and mixing this with other groups of drugs that impair the stability of vitamin 81□. In addition, when making tablets, separation using so-called dry-coated tablets or laminated tablets,
Alternatively, in the case of coated tablets, improvements are made by adding it to the coating layer.

Furthermore, vitamin Bl in the adsorption bundle! Various additives, such as modified food starch, are used to stabilize the food.
Vitamin E3+z adsorption powder (Hoffmann-LaRoche
Inc.

: VITAMIN B 140-1%SD) exists on the market. This adsorption bundle is generally made up of an adsorbent and vitamin B
It is manufactured by spray drying a suspension or solution of Class I2 in water (Japanese Patent Application Laid-Open No. 108224/1983).

Furthermore, for the purpose of stabilization, shellac and macrogol 6 were added.
Microencapsulation by emulsion method using 000 has been proposed by Gupta et al. (R, G, G
upta and B, C, Rao, Drug D
evel, and lnd, Pharm,, 1
1(1), 41-53 (1985)].

In addition, vitamin 13 using pregelatinized starch as an adsorbent
A +z formulation has also been proposed (Japanese Patent Application No. 28245/1983).

Other vitamin B12 agents include adsorbates on cation exchange resins (US Pat. No. 2,830,933) and vitamin B1 dispersed in a gelatin matrix.

Problems to be Solved by the Invention As mentioned above, mannitol adsorbent bundles, lactose adsorbent powders, and dicalcium phosphate adsorbent powders have problems in terms of formulation stability. Various complicated formulation steps such as chemization are required.

In addition, spray-dried compositions using modified food starch, compositions using pregelatinized starch, and magellatin matrix require complicated manufacturing techniques, high raw material costs, and require large-scale equipment. The production cost is high because of the high price of the adsorbent itself and the high price of the adsorbent itself. Therefore, it is desired to develop a vitamin B12 composition that solves the following problems.

l) Can be manufactured using simple manufacturing methods and equipment.

2) Stable even when mixed with other agents.

3) Can be directly compressed into tablets by combining with other drugs.

4) It is inexpensive.

Means for Solving the Problems In order to solve the above-mentioned problems, we produced a vitamin B11 composition using an adsorbent made by mixing dextrin with inexpensive starch. It was discovered that a VIG2F 80 composition with excellent formulation stability, which had not been observed before, could be obtained. Based on this knowledge, the present invention was completed.

That is, the present invention provides vitamin Bl! The present invention relates to a vitamin Blj-containing composition in which Blj-class are dispersed in a mixture of starch and dextrin.

Dianocobalamin is a vitamin 81□ class.

Examples include corrinoid compounds such as hydroxocobalamin, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, and coenzyme vitamin E3+z.

As starch, starch granules can be used as they are. Specifically, for example, corn starch,
Examples include potato starch, rice starch, rice starch, and tapioca starch.

Dextrin is obtained by hydrolyzing starch, and various types can be used. Specifically, for example, erythrodextrin.

Examples include acrodextrin and maltodextrin. - Inside the shell, use a dextrin that exhibits a coloration ranging from colorless to brown to red in the iodine reaction confirmation test listed in the Japanese Pharmacopoeia Law, or a dextrin with a molecular weight of about io, ooo or less.

Preferably, commercially available products listed in the Japanese Pharmacopoeia Law can be used.

To make the composition of the invention, first the dextrin and starch are mixed. The mixing ratio is 5 dextrin to the total amount of starch, dextrin, and vitamin B1□.
-30% by weight, preferably 10-20% by weight.

When the dextrin content is less than 5% by weight, the dispersion of vitamin B1□ may not be sufficient, and when it is more than 30% by weight, the particles of the composition become hard, and when the composition is made into a tablet,
Disintegration may deteriorate.

This mixing may be carried out using a conventional solid mixing method to obtain a homogeneous mixture.

Next, the vitamin BI2 compound is dissolved in water or an aqueous organic solvent diluted with water. This liquid is added to the starch/dextrin mixture prepared previously, mixed so that the vitamin B12 compound is uniformly dispersed, and then dried.

Mixing is carried out using, for example, a stirring granulator or a transfer granulator.
You can do it in the normal way.

Alternatively, the mixture may be fluidized in a fluidized bed using a fluidized granulator, and a solution of the vitamin B1□ compound may be spray-dried.

The amount of vitamin 81□ compound to be used is 0.0% relative to the total amount of starch, dextrin, and vitamin B12.
05-120% by weight, preferably 0.1-120% by weight
It is.

When making a vitamin B12 compound into a solution,
It is preferable to adjust the concentration to below the saturation concentration of vitamin Blf in water. Generally, an aqueous solution of 8% (W/V) or less,
Preferably, the aqueous solution is in the range of 0.4 to 7% (W/V).

When using an aqueous solvent diluted with water as described above,
An organic solvent may be further added to this. In particular, the use of ethanol facilitates the dispersion of vitamin E3+g.

Furthermore, when fluidized granulation is performed, a dilute aqueous solution is generally used, but the amount of solution may be selected as appropriate depending on the equipment used.

The granules obtained as described above may be sized, if necessary.
The desired preparation can be prepared by pulverization or the like.

For blending with other agents, powder having a particle size of 100 μm or less is preferable.

Effects of the Invention The vitamin B12-containing composition of the present invention is itself stable, and by using a starch-dextrin mixture, it can be produced by a simple and ordinary method, and no special equipment is required.

Also, if Kigumi products are used in the compounding agent, the vitamin BlZs are stable and there is very little change in quality over time, such as decrease in content.

Furthermore, since the vitamin B12-containing composition of the present invention contains dextrin, the composition of the present invention can be used together with granules that can be directly compressed such as other commercially available vitamin Bl, vitamin B 6 + vitamin C, etc. It can be directly compressed into tablets by simply mixing. This is an effect that cannot be obtained with starch alone.

Furthermore, since the composition of the present invention can be produced using commercially available starch and dextrin, the raw materials themselves do not require any special modification. Therefore, the price can be reduced and it is very advantageous for industrial production.

Examples and Experimental Examples [Example 11 Tapioca starch 23.94 to 9 and dextrin (
6 kg of the product listed in the Japanese Pharmacopoeia Law was placed in a 30 gallon pony mixer and mixed for 10 minutes to obtain a tapioca starch/dextrin mixed powder.

Separately, 60 g of dianocobalamin was dissolved in 4.5 Q of pure water, and 4.5 Q of ethanol was further added and mixed.

This solution was added to a pony mixer containing tapioca starch/dextrin mixed rice and kneaded for 20 minutes to obtain granules.

This granulated product was vacuum dried at 40°C to remove water and ethanol, and a dried product was obtained.

This dried product was crushed with an atomizer equipped with a 1 mm fJ screen, and 500 times dianocobalamin powder (0,
2% by weight) was obtained.

The appearance of the obtained triturate was a red powder, and the loss on drying was 6.6%.
Met.

[Example 2] Put 7.99 kg of tapioca starch into a 75L-super mixer, and add dextrin (product listed in the Japanese Pharmacopoeia Law) to it.
2 kg was added and mixed for 1 minute to obtain tapioca starch/dextrin mixed rice.

Separately, add 109 parts of dianocobalamin to 1 part of pure water! 1 of the solution, and further added ethanol 125Q and mixed.

This solution was added to a super mixer containing tapioca starch/dextrin mixed rice and kneaded for 10 minutes to obtain granules.

This granulated product was vacuum dried at 40°C to remove water and ethanol, and a dried product was obtained.

This dried product was crushed with an atomizer equipped with an lmm screen, and the 1000 times dianocobalamin powder (0,
1% by weight) was obtained.

The appearance of the obtained triturate was a red powder, and the loss on drying was 4.5%.
Met.

[Example 31] 7.99 kg of corn starch was placed in a 75 L-super mixer, 2 kg of dextrin (listed in the Japanese Pharmacopoeia Act) was added thereto, and mixed for 1 minute to obtain corn starch/dextrin mixed rice.

Separately, dianocobalamin log was dissolved in pure water 12512, and ethanol 125Q was further added and mixed.

This solution was added to a super mixer containing corn starch/dextrin mixed rice and kneaded for 10 minutes to obtain a granulated product.

This granulated product was vacuum dried at 40°C to remove water and ethanol, and a dried product was obtained.

This dried product was crushed with an atomizer equipped with an lmm screen, and the 1000 times dianocobalamin powder (0,
1% by weight) was obtained.

The appearance of the obtained triturate was a red powder, and the loss on drying was 5.6%.
Met.

[Example 4] 790 g of corn starch and dextrin (Japanese Pharmacopoeia Law) 2009 were placed in a vertical granulator and mixed to obtain corn starch/dextrin mixed rice.

Separately, dianocobalamin 109 and pure water 150!1112
150 mQ of ethanol was further added and mixed.

This solution was added to a vertical granulator containing corn starch/dextrin mixed rice and kneaded to obtain a granulated product.

This granulated product was vacuum dried at 40°C to remove water and ethanol, and a dried product was obtained.

This dried material was pulverized with a power mill equipped with a 1m+m-screen, and 100 times dianocobalamin powder (1,0
% by weight) was obtained.

The appearance of the obtained triturate was a red powder, and the loss on drying was 5.5%.
Met.

[Example 5] 890 g of corn starch and dextrin (product listed in the Japanese Pharmacopoeia Law) 509 were placed in a fluidized granulator and mixed.

Separately, 10 g dianocobalamin and 50 g dextrin
A solution was prepared by dissolving g in 250 md of pure water.

This solution was dried while being sprayed into a fluidized granulator containing corn starch and dextrin to obtain granules.

This granulated material was pulverized with a power mill equipped with a 1m+oI screen, and the granulated material was crushed with a 100x powder of Cyanocovar 2F (1,0
% by weight) was obtained.

The appearance of the obtained triturate was a red powder, and the loss on drying was 7.1%.
Met.

[Method for quantifying vitamin 812] A sample solution obtained by extracting vitamin 812 with a 0.1% phosphoric acid/methanol mixture (3:l volume ratio) was quantified by liquid chromatography.

The quantitative conditions were as follows: A separation column packed with octadecylsilylated silicage J was used, and 0-05 mo
l Ammonium dihydrogen phosphate solution/methanol mixture (7:
3 volume ratio) was used as a mobile phase, and the wavelength was 550 nm.

[Experimental Example 1] Stability of vitamin B12 type powder itself 10 g of the multipliers obtained in Examples 1 to 5 (100 g of dianocobalamin in the case of 1000x powder).

100mg for 100x, 2 for 500x
(equivalent to 0 mg) in a glass bottle and heated to 60'C or 5Q'C! , RH 68% (relative humidity).

For experiments conducted at 60°C, the glass bottle was tightly capped and heated to 50'C, R.
When H was 68%, the glass bottle was opened.

Samples were taken out after storage for 2 weeks and dianocobalamin content, loss on drying, and change in appearance were measured.

The results are shown in Table 1.

In addition, as a comparative example, commercially available vitamin 88.0.1% loss (
Manufactured by Roche, VITAMIN L 0.1%SD
5316Roche Chemical Division) was used.

Table 1 Unit: % (residual rate from initial) [Experimental example 2] Combination stability example 1 with ascorbic acid
509 (1000 times powder, 50 mg as dianocobalamin) obtained in step 5.

500n+g for 100x powder, loomg for 500x powder) with 1OO9 of ascorbic acid, put 109 of each of the mixture into a glass bottle, and add 60
Stored at °C.

This experiment was conducted with a glass bottle tightly closed.

Samples were taken out after storage for 2 weeks and dianocobalamin content, loss on drying, and change in appearance were measured.

The results are shown in Table 2.

In addition, as a comparative example, commercially available vitamin B, 0.1% loss (
(manufactured by Roche) was used.

Table 2 Unit 2% (residual rate from initial) [Experimental Example 3] Combination stability with vitamin B1 and vitamin B 50mg as cobalamin.

(equivalent to 500,111 g in case of 100 times defeat, 100 mg in case of 500 times defeat) with 130 g of thiamine nitrate and 10 g of pyridoxine hydrochloride, put each log of the mixture into a glass bottle, and heated at 60'O or 50°C, RH.
Stored at 68% (relative humidity).

For experiments conducted at 60°C, the glass bottle was tightly capped and heated to 50'O.
When the RH was 68%, the glass bottle was opened.

Samples were taken out after storage for 2 weeks and dianocobalamin content, loss on drying, and change in appearance were measured.

The results are shown in Table 3.

In addition, as a comparative example, commercially available vitamin B1□0.1% loss (
(manufactured by Roche) was used.

Table 3 Unit 2% (survival rate from initial)

Claims (3)

[Claims] (1) A vitamin B_1_2-containing composition in which vitamin B_1_2 is dispersed in a mixture of starch and dextrin. (2) Starch, dextrin and vitamin B_1_
Vitamin B_1_2 is 0.05 to 1 for the total amount of 2.
．． The composition according to claim 1, wherein the content is 0% by weight. (3) The composition according to claim (1) or (2), which is in the form of granules or powder.